A Phase I-II Study of α-Galactosylceramide-Pulsed IL-2/GM-CSF-Cultured Peripheral Blood Mononuclear Cells in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer

Abstract

To evaluate the safety, immune responses, and antitumor responses after the administration of α-galactosylceramide (αGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 × 109/m2) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-γ-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-γ-producing cells (≥2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-γ-producing cells that result from αGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…7,15,16,21,30,31 Although clinical trials examining NKT cell activation therapies in patients with advanced/recurrent disease have reported few cases of objective tumor regression, tumors tended to remain stable without the appearance of new metastatic foci. 15,[17][18][19][20]35 This suggests that NKT cell activation therapy might be more effective at targeting metastatic disease than primary tumors. Since primary breast cancer tumors are effectively treated by surgical resection, and disseminated metastasis remains the primary cause of mortality, 50 NKT cell activation therapy presents a promising therapeutic avenue.…”

“…We focused on a-GalCer in this study because it has been used extensively in human clinical trials where it has been shown to be safe and well tolerated. 17,18,20 The ability of free a-GalCer to protect from metastasis was transient, suggesting that multiple treatments or higher doses would be needed therapeutically. However, these strategies are limited by the induction of anergy and toxicity, respectively.…”

“…10,54 Administration of a-GalCer or the Th1 skewing analog a-CGalCer significantly reduced tumor metastasis at early timepoints, whereas the Th2 skewing analog OCH had no significant effect. While Th1 skewing is important for tumor control in mouse models, 31,33,34 and elevated IFNg production is associated with prolonged survival in clinical trials, 20,35 we previously found that OCH treatment effectively controlled metastasis of B16 melanoma and Lewis lung carcinoma cells to the liver in C57BL/6 mice. 7 It is likely that the ratio of Th1:Th2 cytokines ultimately impacts tumor control, and differences in immune skewing between BALB/c and C57BL/6 mice could influence the effect of OCH.…”

“…13,14 Preclinical and clinical studies have shown that NKT cell activation with exogenous glycolipids provides significant protection from tumor progression. [15][16][17][18][19][20] Although several studies have examined the role of NKT cell activation on primary mammary carcinoma growth, 21,22 the potential therapeutic benefits of NKT cell activation in metastatic breast cancer have not been explored in detail. The aim of this work was to examine the role of NKT cell activation in a postsurgical breast cancer metastasis model.…”

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

“…In addition, based on our previous study of postinfarct heart failure [17], αGC administration may attenuate also LV remodeling and reduce mortality after MI. To date, several clinical trials (Phase I/II) using activated iNKT cells by αGC have been conducted in patients with cancer [45][46][47][48][49]. No severe adverse events were observed in these trials.…”